The study cohort consisted of a combined sample from two large osteoarthritis studies – the Framingham Osteoarthritis Study and the MOST Study.
The Framingham sample was composed of two separate groups, 1) members of the Framingham Heart Study Offspring Cohort and 2) a newly recruited cohort from the town of Framingham, Massachusetts (Community Cohort). Participants in this combined group, designated the Framingham OA Study Cohort, were examined between 2002 and 2005.
The Framingham Heart Study Offspring Cohort participants included surviving descendants (and spouses of descendants) of the Original Framingham Heart Study cohort subjects20
. As part of a study of the inheritance of OA, selected participants were originally examined in 1992–94. Members of this group were identified as potential participants of the current study. All were contacted by telephone and invited to participate in the study. A validated survey instrument21
supplemented by questions about medication use that would reflect treated rheumatoid arthritis was used to screen potential subjects. Those who screened positively for rheumatoid arthritis were excluded.
The newly recruited participants to the Framingham OA Study Cohort (Community Cohort) were drawn from a random sample of the Framingham, Massachusetts community. Flyers were hung in public areas to increase awareness of the study, which focused on health including bone health, foot health and arthritis. Participants were recruited using random digit dialing and census tract data to ensure inclusion of a representative sample of the community. To be included, subjects had to be at least 50 years old and ambulatory (use of canes and walkers was allowed). Participants with bilateral total knee replacements (TKR) or a positive screen for rheumatoid arthritis as above21
were excluded. In neither group was participant selection based on the presence or absence of knee OA or knee pain.
In order assess if a subject had experienced previous knee injury the following question was asked: “Have you ever injured your knee badly enough to limit your ability to walk for at least 3days?”
Based on an agreement with the parent Framingham Heart Study to limit the respondent burden of the Framingham Offspring subgroup, only those who answered affirmatively to the question, “In the past 30 days, have you had any pain, aching or stiffness in either of your knees?” underwent MRI of the knee(s) In these subjects, both knee MRIs were read when acquired. For the community sample, all subjects had bilateral knee MRIs whether or not they had knee symptoms but, because of funding limitations, only the right knee was read. Those participants with MRI contraindications were not scanned, and those with one TKR had only their native knee scanned.
All studies were performed with a 1.5T MRI system (Siemens, Mountain View, CA) using a phased array knee coil. A positioning device was used to ensure uniform placement of the knees. Imaging sequences included: sagittal (TR 3610 ms, TE 40 ms, 3.5 mm slice thickness, 0 mm interslice gap, 32 slices, 256 × 256 matrix, 139 mm2 FOV, echo train length 7), axial (TR 3610 ms, TE 40 ms, 3.0 mm slice thickness, 0 mm interslice gap, 20 slices, 256 × 256 matrix, 139 mm2 FOV, echo train length 6) and coronal (TR 3610 ms, TE 40 ms, 3.5 mm slice thickness, 0 mm interslice gap, 30 slices, 256 × 256 matrix, 139 mm2 FOV, echo train length 7) T2-weighted turbo spin echo sequences with fat suppression, and a sagittal T1-weighted spin echo sequence without fat suppression (TR 475 ms, TE 24 ms, 3.5 mm slice thickness, 0 mm interslice gap, 32 slices, 256 × 256 matrix, 139 mm2 FOV).
Approval for the study was obtained from the Boston University Medical Center Institutional Review Board (IRB).
The MOST study is an NIH-funded prospective epidemiological study of 3,026 persons aged 50 to 79 years, with a goal of identifying risk factors for incident and progressive knee OA in a sample with either OA or at high risk of developing it. Those considered at high risk included persons who were overweight or obese, those with knee pain, aching or stiffness on most of the last 30 days, a history of knee injury that made it difficult to walk for at least one week, or previous knee surgery.
Subjects were recruited from two U.S. communities, Birmingham, Alabama and Iowa City, Iowa through mass mailing of letters and study brochures, supplemented by media and community outreach campaigns. The study protocol was approved by IRB's at the University of Iowa, University of Alabama, Birmingham, University of California, San Francisco and Boston University Medical Campus.
Subjects were excluded from MOST if they screened positive for rheumatoid arthritis21
, had ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, had kidney problems requiring hemo- or peritoneal dialysis, a history of cancer (except for non-melanoma skin cancer), had or planned to have bilateral knee replacement surgery, were unable to walk without the help of another person or walker, or were planning to move out of the area in the next three years. History of past knee injury was assessed in the same manner than Framingham study.
MRIs in MOST were obtained in both knees with a 1.0T dedicated MR system (OrthOne™, ONI Medical Systems, Inc., Wilmington, MA) with a circumferential extremity coil using fat suppressed fast spin echo proton density (PD) weighted sequences in two planes, sagittal (TR 4800 ms, TE 35 ms, 3 mm slice thickness, 0 mm interslice gap, 32 slices, 288 × 192 matrix, 140 mm2 FOV, echo train length 8) and axial (TR 4680 ms, TE 13 ms, 3 mm slice thickness, 0 mm interslice gap, 20 slices, 288 × 192 matrix, 140 mm2 FOV, echo train length 8) and a STIR sequence in the coronal plane (TR 6650 ms, TE 15 ms, TI 100 ms, 3 mm slice thickness, 0 mm interslice gap, 28 slices, 256 × 192 matrix, 140 mm2 FOV, echo train length 8). Only one knee per patient was randomly selected to be read when both knees had been scanned and had available MRI readings.
Radiographic assessment in both studies
In both studies, all subjects underwent weight-bearing posteroanterior (PA) fixed flexion knee radiographs using the protocol by Peterfy et al. and a plexiglass positioning frame (SynaFlexer™)22
A musculoskeletal radiologist and a rheumatologist experienced in reading study films, both blinded to case/control status and clinical data, graded all PA films according to the Kellgren and Lawrence (K/L) scale23
. If readers disagreed on the presence of radiographic OA, the film readings were adjudicated by a panel of 3 readers.
Out of the above defined study samples, we excluded all subjects who exhibited any sign of tibiofemoral radiographic osteoarthritis (K/L grades 1 through 4) and retained only knees with K/L Grade 0.
MRI assessment for both studies
In both studies two musculoskeletal radiologists (for the Framingham study FWR and AM; for the MOST study FWR and AG), blinded to clinical and x-ray data, read the MRIs.
Meniscal integrity was graded according to the Whole-Organ MRI Score (WORMS) method17
. The anterior horn, body segment, and the posterior horn of the medial and lateral menisci were scored separately from 0–4: 0 = intact; 1 = minor radial or parrot-beak tear; 2 = non-displaced tear; 3 = displaced tear; 4 = complete maceration or destruction (Inter-observer reliability for meniscal scoring in the Framingham study: weighted-kappa 0.70, 95% confidence intervals [0.64,0.76]; in the MOST study: weighted-kappa 0.79, 95% confidence intervals [0.59,0.97]). According to the WORMS system meniscal damage
was defined as a tear, maceration, and (or) destruction (=any grades ≥1 on scale above). The readers regarded intrameniscal signal as a meniscal tear only when it communicated with the meniscal inferior or superior margin on at least two slices. Intrameniscal signal alterations that did not fulfill the aforementioned criteria of a tear were scored as no tear (Grade 0).
Joint effusion was graded from 0 to 3 in terms of the estimated maximal distention of the synovial cavity according to the WORMS scoring system: 0=normal; 1=<33% of maximum potential distention; 2=33%–66% of maximum potential distention; 3=>66% of maximum potential distention. Joint effusion was defined as any joint effusion score ≥1. Image examples of the different effusion scores are presented in . (Inter-observer reliability for effusion scoring in the Framingham study: weighted-kappa 0.70, 95% confidence intervals [0.62,0.79]; in the MOST study: weighted-kappa 0.73, 95% confidence intervals [0.53,0.92]).
We first computed the overall prevalence of meniscal damage in the study sample. We then evaluated the association between meniscal damage and presence of joint effusion using logistic regression adjusting for gender, age, body mass index (BMI) and study site, with knees without meniscal damage as the reference group. Before combining the subsamples we examined the data to be sure that results were consistent in both sites. A subanalysis was performed concerning joint effusion present in knees with meniscal pathology in only one or in both, the medial and lateral tibiofemoral compartments. An additional analysis was performed for knees with no cartilage damage (WORMS score ≤1) in the tibiofemoral and patellofemoral compartments.